甲磺酸萘莫司他与吉西他滨联合化疗靶向NF-κB激活治疗胰腺癌。
Combination chemotherapy of nafamostat mesilate with gemcitabine for pancreatic cancer targeting NF-kappaB activation.
作者信息
Uwagawa Tadashi, Chiao Paul J, Gocho Takeshi, Hirohara Shouichi, Misawa Takeyuki, Yanaga Katsuhiko
机构信息
Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
出版信息
Anticancer Res. 2009 Aug;29(8):3173-8.
PURPOSE
Gemcitabine is currently the standard first-line chemotherapeutic agent for pancreatic cancer. However, chemoresistance to gemcitabine because of gemcitabine-induced nuclear factor-kappaB (NF-kappaB) activation has been reported. We previously reported that the synthetic serine protease inhibitor nafamostat mesilate inhibited NF-kappaB activation and induced apoptosis of pancreatic cancer cells. In this study, whether or not nafamostat mesilate could enhance the anticancer effect of gemcitabine was investigated.
MATERIALS AND METHODS
NF-kappaB activation in pancreatic cancer cells treated with various agents was examined by electrophoretic mobility shift assay (in vitro) and immunohistochemistry by investigating the location of p65 in cancer cells (in vivo). Apoptosis of the cancer cells treated with agents was examined by flow cytometry.
RESULTS
Nafamostat mesilate inhibited gemcitabine-induced NF-kappaB activation, enhanced apoptosis by gemcitabine and suppressed pancreatic tumor growth. Interestingly, the combination treatment improved the body weight loss of mice induced by gemicitabine.
CONCLUSION
This combination chemotherapy could be a potential novel strategy for pancreatic cancer.
目的
吉西他滨目前是胰腺癌的标准一线化疗药物。然而，已有报道称由于吉西他滨诱导核因子-κB（NF-κB）激活而导致对吉西他滨产生化疗耐药性。我们之前报道过，合成丝氨酸蛋白酶抑制剂甲磺酸萘莫司他可抑制NF-κB激活并诱导胰腺癌细胞凋亡。在本研究中，我们调查了甲磺酸萘莫司他是否能增强吉西他滨的抗癌效果。
材料与方法
通过电泳迁移率变动分析（体外）以及通过研究癌细胞中p65的定位进行免疫组织化学（体内）来检测用各种药物处理的胰腺癌细胞中的NF-κB激活情况。通过流式细胞术检测用药物处理的癌细胞的凋亡情况。
结果
甲磺酸萘莫司他抑制吉西他滨诱导的NF-κB激活，增强吉西他滨诱导的细胞凋亡并抑制胰腺肿瘤生长。有趣的是，联合治疗改善了吉西他滨诱导的小鼠体重减轻。
结论
这种联合化疗可能是一种治疗胰腺癌的潜在新策略。
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